Method and compound for treatment of menopausal symptoms

ABSTRACT

The subject invention describes a method of use of Ropinirole™ to alleviate and control menopausal symptoms in women, and in particular, hot flashes. The invention describes the use of Ropinirole as a dopamine agonist with affinity for the dopamine D 2 , D 3 , or D 4  receptors. Ropinirole may also be used to treat menopausal symptoms in conjunction with Tizanidine™ to further reduce the effects menopausal symptoms by providing a sedative and muscle relaxant effect which aids in sleep. The combination of Ropinirole and Tizanidine provides a useful new compound for treatment of menopausal symptoms that are most disruptive to the functioning in activities of daily living.

TECHNICAL FIELD

The subject invention relates to treatments and treatment methods ofmenopausal symptoms including hot flashes and sleep disturbanceassociated with menopause. Menopause and menopausal symptoms arecontrolled within the body by hormones which transmit information forthe production or inhibition of various molecules which act to producemenopausal symptoms. The subject invention provides for a novelcombination of drugs and a new method of use which simulate the effectof naturally occurring neurotransmitters and thus aid in controllingmenopausal symptoms.

BACKGROUND OF THE INVENTION

Menopause reflects the loss of function of the ovaries which affects allwomen at certain ages of their lifetimes. It typically begins naturallyin middle age (late 40s through early 50s) over a period of time.However, menopause may occur more abruptly and earlier in certainmedical conditions or when induced through surgical removal of theovaries. The natural symptoms of menopause usually begin slowly, duringa phase described as menopausal transition or perimenopause, and can bedevastating. These menopausal symptoms include irregular menses, hotflashes and night sweats, sleep disruption, atrophy of reproductivetissues, increased stress, tenderness of the breast, vaginal dryness,mood changes, forgetfulness, and sometimes osteoporosis and heartdisease.

One of the most prevalent symptoms is the typical “hot flash” which is awoman's perception of a sudden increase in body temperature. The hotflash is the result of vascular changes which permit rapid increasedblood flow through vessels. During a hot flash, the body temperaturerises rapidly and then only slowly returns to its normal bodytemperature.

Various methods have been used to treat menopausal symptoms, and inparticular, hot flashes. Hormonal Replacement Therapy (HRT) is a form oftreatment which supplements naturally occurring hormones in the body. Atnormal levels, estrogen and progestin counter the effects of otherhormones, such as luteinizing hormone (LH) and follicle stimulatinghormone (FSH). During menopause, as estrogen and progestin levels arereduced, and levels of LH and FSH are found at high levels andmenopausal symptoms become more apparent.[http://en.wikipedia.org/wiki/Menopause (accessed Feb. 2, 2012)]. HRTtreatment aims to supplement levels of estrogen and progestin to reducelevels of LH and FSH and thus reduce menopausal symptoms.

Increased levels of estrogen, though, create a risk of a number of otherhealth risks including cancer, heart attack, and strokes. [Decline inuse of hormone therapy among postmenopausal women in the United Kingdom,Menopause 14 (3 Pt 1): 462-7; Differences in menopausal hormone therapyuse among women in Germany between 1998 and 2003, BMC Womens Health 7:19; Prescribing of hormone therapy for menopause, tibolone, andbisphosphonates in women in the UK between 1991 and 2005, Eur. J. Clin.Pharmocol. 63 (9): 843-9]. Accordingly, HRT treatment may createpotentially undesirable consequences far more devastating that theeffects of menopausal symptoms, such as stimulating the growth ofmalignant cells.

Use of selective serotonin re-uptake inhibitors (SSRIs) is anothermethod which has been used to treat menopausal symptoms. SSRIs havetypically been used as antidepressants. SSRIs increase levels ofserotonin by inhibiting its re-uptake into presynaptic cells. In theory,by increasing the levels of serotonin in the brain, the claimed benefitsachieved as an anti-depressant, i.e. improving mood and promoting sleep,also serve to alleviate menopausal symptoms. However, the efficacy ofSSRIs has been disputed. [Serotonin and Depression: A Disconnect betweenthe Advertisements and the Scientific Literature, PLoS Medicine 2 (12):e392].

Selective Estrogen Receptor Modulators (SERMs) is another category ofdrugs which have been used to treat menopausal symptoms. These drugs actas agonists or antagonists to estrogen receptors throughout the body.However, it has been reported that most SERMs actually increase hotflashes. [http://en.wikipedia.org/wiki/Menopause (accessed Feb. 2,2012). See also Menopausal Symptoms, Clin. Exp. Obstet. Gynecol. 31 (2):123-6]. Other drugs such as anti-seizure medications (i.e., gabapentin),and blood pressure medications (i.e., clonidine), have also been used totreat menopausal symptoms. [http://en.wikipedia.org/wiki/Menopause(accessed Feb. 2, 2012)]. The mechanism of action of these agents ispoorly understood, and the effectiveness of these treatments isdisputed. [Gabapentin for hot flashes in 420 women with breast cancer: arandomized double-blind placebo-controlled trial, Lancet.366(9488):818-24; Positive efficacy data from a phase 2 trial ofgabapentin extended-release in the treatment of menopausal hot flashes,Menopause, 15(6): 1225; Nonhormonal Therapies for Menopausal HotFlashes: Systematic Review and Meta-analysis, JAMA, 295(17):2057-71].

Natural regulation of menstrual cycles is controlled by complexinteractions between various hormones and hormone producing glandswithin the body. The hypothalamus in the brain is a primary regulator ofmenstrual cycles. Hormones produced by the hypothalamus in theregulation of menstrual cycles include dopamine and prolactin. Dopamineinhibits the release of prolactin, while Thyrotropin Releasing Hormone(TRH) promotes the release of prolactin. Dopamine receptors in the bodymay be grouped into categories producing different effects depending onthe type of receptor to which dopamine binds. Receptors of groups D₂,D₃, or D₄ produce effects contrary to those of group D₁ and D₅. [D2Dopamine receptor subtype mediates the inhibitory effect of dopamine onTRH-induced prolactin release from the bullfrog pituitary, Gen. Comp.Endocrinology, 168(2):287-92; Dopamine D₁ receptor analogues actcentrally to stimulate prolactin secretion in ewes, J. Endocrinology,137:457-64]. Dopamine binding to receptors D₂, D₃, or D₄ in thehypothalamus will inhibit the production of prolactin, and also inhibitthe pulsatile production of Gonadotropin Releasing Hormone (GnRH) inestrogen deficient females [Regulation of Gonadotropin-Releasing Hormone(GnRH)-Receptor Gene Expression in Tilapia: Effect of GnRH and Dopamine,Biology of Reproduction, 70:1545-51]. It is the latter effect which inturn inhibits the production of LH and FSH in the pituitary gland in theestrogen deficient state of perimenopause and menopause. LH and FSHstimulate various functions in the reproductive and menstrual cycles. Tothe contrary, dopamine binding to the D₁ and D₅ receptors will stimulatethe production of prolactin and will increase the production of GnRHthus leading to an increase in hot flashes. [D2 Dopamine receptorsubtype mediates the inhibitory effect of dopamine on TRH-inducedprolactin release from the bullfrog pituitary, Gen. Comp. Endocrinology,168(4287-92].

LH and FSH are found at high levels during menopause. When levels ofestrogen are higher, prior to menopause, estrogen provide a feedbackloop which serves to limit the production of LH and FSH. However, duringmenopause, when levels of estrogen drop, levels of LH and FSH Increase.Studies have shown that LH and FSH act as vasodilators which increasethe flow of blood throughout the vessels. The increase in the flow ofblood causes symptoms of hot flashes.

Drugs which activate a receptor to produce a pharmacological responseare called agonists. These drugs may mimic the effect of the naturallyoccurring substance. An antagonist counteracts the pharmacologicaleffect of a drug or a naturally occurring substance. U.S. Pat. No.7,645,750 describes the use of certain drugs in the treatment ofmenopausal symptoms, in particular, hot flashes. In particular, thepatent describes the use of risperidone, quetiapine, clozapine,olanzapine, aripiprazole, ziprasidone, zotepine, or 9-hydrozyrisperidoneas serotonin type 2A (5-HT₂₄) and dopamine type 2 (D₂) receptorantagonists. However, the efficacy of administering these drugs to treatmenopausal symptoms has been disputed. [The Safety of Verlipride, ExpertOpin. Drug Saf. 5(5):695-71]. As is discussed herein, the subjectinvention describes treatment with a dopamine agonist to provide reliefof menopausal symptoms. Accordingly, it follows that treatment with adopamine antagonist provides contrary results.

Ropinirole™ is a dopamine agonist manufactured by GlaxoSmithKline,Cipla, and Sun Pharmaceutical. The chemical formula for Ropinirole is4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one as follows:

Ropinirole has typically been used in the treatment of Parkinson'sdisease. It has also been used to treat Restless Legs Syndrome.Ropinirole has high affinity to D₂, D₃, or D₄ dopamine receptors withthe highest affinity for D₂. [Preclinical Pharmacology of Ropinirole(SK&F 101468-A) a Novel Dopamine D2 Agonist, Pharmacology Biochemistry &Behavior 38: 147-154]. However, Ropinirole has not previously beenstudied or used in the treatment of menopausal symptoms except by theinventor as discussed herein to illustrate the utility of the subjectinvention.

The other symptom after hot flashes that is equally, if not more,damaging to the daily functioning of a menopausal woman is sleepdeprivation. Tizanidine is the molecule that can most effectivelyaddress this symptom. Tizanidine™ (a/k/a Zanaflex™), chemical formula5-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)benzo[c][1,2,5]thiadiazol-4-amine,is a drug compound which has traditionally been used as a musclerelaxant. The molecular structure of Tizanidine is as follows:

As such, it has been used in the treatment of disorders such as multiplesclerosis, spastic diplegia, back pain, and other problems related tothe spine and central nervous system. [A Practical Overview OfTizanidine Use For Spasticity Secondary To Multiple Sclerosis, Stroke,And Spinal Cord Injury, Curr Med Res Opin 24(4425-39]. Tizanidine isalso an excellent sedative [http://en.wikipedia.org/wiki/Tizanidine(accessed Jan. 8, 2012)]. Tizanidine has not previously been consideredor used in the treatment of menopausal symptoms of sleep disturbanceexcept by the inventor as discussed herein to illustrate the benefits ofthe subject invention.

Given the risk of some of the current methods of treatment, and thefailure of those methods to adequately treat and control menopausalsymptoms such as hot flashes and sleep deprivation, there remains a needfor improved means of addressing and treating these symptoms. Thesubject invention addresses these concerns and provides a newcombination of drugs and methods of use which previously have notdistinctly been shown to reduce the severity of hot flashes andmenopausal symptoms of sleep disruption.

SUMMARY OF THE INVENTION

Two of the most incapacitating symptoms of menopause are hot flashes anddisruption of the normal sleep pattern. Although there have been manyattempts to address each of these symptoms individually, there is nosingular product that addresses both problems.

The subject invention describes a novel and new use of Ropinirole toalleviate and control menopausal symptoms in women, and in particular,hot flashes. The invention describes the use of Ropinirole as a dopamineagonist with affinity for the dopamine D₂, D₃, or D₄ receptors. Clinicalstudies submitted have shown that treatment with Ropinirolesignificantly reduced hot flashes and menopausal symptoms. It isbelieved that Ropinirole reduces production of GnRH which in turnreduces production of LH and FSH. The use of Ropinirole as a menopausalsymptom treatment overcomes the limitations of the prior art as it doesnot pose some of the significant health effects and side effectsassociated with HRT therapy and use of anti-depressant medication suchas SSRIs. Further, the clinical trials submitted have shown the use ofRopinirole to have a much greater efficacy than traditional menopausetreatments in the prior art described above.

Additionally, Tizanidine, when used in combination with Ropinirole,further reduces the effects menopausal symptoms by providing a sedativeand muscle relaxant effect which aids in sleep. The muscle relaxanteffect further impacts vasodilatlon which may influence the response tohot flashes. This new combination of drugs addresses problems associatedwith menopausal symptoms and loss of sleep in one medication. Mostcritically, it is safe for women who have any medical issues related totaking hormone replacement therapy, such as hormone sensitive breastcancer patients, ovarian cancer patients and uterine cancer patients,those with clotting disorders, women with a history of hypertension andthose women who smoke.

DETAILED DESCRIPTION OF INVENTION

Hot flashes of menopause are vasomotor events characterized by suddenbursts of intense warmth in the chest, which may ascend to the neck andface. This feature is often accompanied by profuse sweating, skinblotching and possibly even palpitations and anxiety. Estimates suggesta prevalence of 75% in postmenopausal women, with an onset of one to twoyears prior to menopause and a duration of six months to five years.

Hot flashes can be particularly disruptive at night, initially causingdrenching sweats followed by a sensation of cold, interrupting sleepseparately from the sleep disturbance of menopause.

During the day, hot flashes can impede an affected individual's abilityto function effectively with negative consequences on job performance,quality of life and self-esteem. Although generally appreciated as acondition affecting women, hot flashes can also affect as many as 75% ofmen following hormonal ablation therapy in the treatment of prostatecancer.

Although the precise mechanism causing hot flashes remains unknown atpresent, their onset occurring in concert with the withdrawal of endorgan hormones, such as estrogen in the female and testosterone in themale, suggests a causal relationship. This is supported by theresponsiveness of resolution of symptoms by women treated with HormoneReplacement Therapy (HRT).

Unfortunately, efforts to treat hot flashes in women with HRT, althoughgenerally successful in 80-90% of women, are now also recognized toplace women with a personal or family history of breast cancer, ovariancancer, uterine cancer, venous thromboembolism, cardiovascular disease,stroke or a positive smoking history, at increased risk.

Women who undergo rapid end organ hormonal withdrawal due tomedical/surgical menopause, such those undergoing total abdominalhysterectomy, or survivors of either breast cancer or ovarian cancersubjected to hormonal blocking therapies (aromatase inhibitors to blockhormone synthesis or tamoxifen to block hormone receptors), areinherently more sensitive to the development of hot flashes.

Withdrawal of end organ steroid hormones are accompanied by apredictable rise in pituitary gonadotrophins. In women there is ameasureable rise in luteinizing hormone (LH) and follicle stimulatinghormone (FSH). Factors contributing to this increase are not only thedecline in end organ steroid hormones, but the impact of changes inother relevant molecules such as inhibin.

Efforts to control hot flashes have initially focused primarily on HRT,with the goal of restoring estrogen to suppress thehypothalamic-pituitary-gonadal axis through which the hot flashes arebelieved to be mediated. Due to the side effects of HRT, alternativeshave been sought over the course of the past decade. Although naturalsupplements have been advocated, these tend to be rich inphytoestrogens, so they are predisposed to the same concerns which havedissuaded the regular use of HRT.

In contrast, with the availability of later generation dopaminergicagonists such as Ropinirole, there is now the opportunity to intervenein the putative hormonal feedback loop without the use of hormones. Justas dopamine can interfere with the release of the pituitary hormoneprolactin, a dopamine agonist may also impede the release of thehypothalamic gonadotrophic hormone, GnRH. Ropinirole is a dopamineagonist with full intrinsic activity at the D₂ and D₃ dopamine receptorsubtypes, binding with higher affinity at the D₃ than to the D₂ or D₄receptor subtypes. It impacts the biofeedback path to control GnRH, andreduces hot flashes. The mechanism of action is postulated to bemediated through the down-regulatory role of dopamine on prolactin andgonadotropin releasing hormone, which would influence the pulsatileunbridled release of LH and FSH of menopause. Ropinirole is awell-tolerated medication, with an excellent safety profile.

Tizanidine is a muscle relaxant which further aids in the reduction ofhot flashes. Tizanidine is also used as an excellent sedative. Incombination with Ropinirole, these drugs effectively treat problemsassociated with menopausal symptoms and loss of sleep in one medication.In addition, these drugs are safe for women who have any medical issuesrelated to taking hormone replacement therapy, such as hormone sensitivebreast cancer patients, ovarian cancer patients and uterine cancerpatients, those with clotting disorders, women with a history ofhypertension and those women who smoke.

The invention contemplates that various forms may be used to administerthis combination of Ropinirole and Tizanidine. For instance, thesecompounds may be administered in a single pill where separate componentsare combined Into sections of the pill or combined throughout a singlepill. These compounds may also be administered in a liquid format to beadministered orally or intravenously. The compounds may also beadministered in the form of a transdermal patch to be worn on the skin.Another method of drug administration may be inhalation of the drugcompounds. The invention also contemplates that these compounds may beadministered by other known means of administering drug compounds.

Additionally, the invention contemplates that other chemical compoundshaving the properties of Ropinirole or Tizanidine and producing the sameeffects may also be used in place of Ropinirole or Tizanidine. Forinstance, compounds acting as a dopamine agonist and binding at the D₂,D₃, or D₄ dopamine receptors may also be used for relief of menopausalsymptoms, and in particular, hot flashes. Compounds having a sedativeeffect may also be used to provide relief of menopausal symptoms. Thesecompounds may also be used in combination to provide effective relieffrom menopausal symptoms.

Clinical Studies

The efficacy of Ropinirole alone to treat menopausal symptoms has beendemonstrated through studies of treatments of four patients with thesesymptoms. Relief from menopausal symptoms was further enhanced throughtreatment with Tizanidine. The patients were treated by escalating thedose of Ropinirole to 4 mg, testing the hypothesis of a dopaminergicallyregulated pathway within the central nervous system which impacts hotflashes. The dopaminergic agonist Ropinirole was escalated from aninitial dose of 0.25 mg to a final dose of 4 mg at bedtime without sideeffects and with the dramatic shutdown of previously intolerable hotflashes of menopause.

Case #1

JK, a 58 year old woman, began experiencing symptoms of insomnia and hadinitially been placed on low dose Hormone Replacement Therapy (HRT)without benefit on her sleep cycle. Despite two changes in dose andformulation of HRT, no significant benefit in sleep cycle was realized.Neither were efforts to treat her sleep problems with standard sedativehypnotics such as zolpidem, zaleplon, temazepam or clonazepam. Hotflashes then began, and became both more frequent and more intense.These were characterized by severe flushing of the face and upper chestwith drenching sweats. Each hot flash would typically last 30-90 secondsand were accompanied by an intense sensation of heat. The hot flashwould then rapidly subside with a sense of being chilled, reflecting thenormal physiologic function of evaporation of perspiration. A period of10 to 90 minutes would elapse before the next hot flash would occur,both during the daytime and throughout the night. It was common forthere to be between 20 to 30, and as many as 40 hot flashes over thecourse of a day at their peak in frequency, although not all would be ofthe same intensity.

Treatment was initiated with Tizanidine, a non-selectivealpha-2-adrenergic agonist, for the purpose of providing a sleep aide.Tizanidine is available as a scored 4 mg tablet that can easily bebroken into four 1 mg portions. Therefore, the initial dose provided was1 mg at bedtime, and the dose was raised as needed, every fourth day, toa maximum of 8 mg, if needed, usually at bedtime. However, if themaximum of 8 mg was not taken at bedtime, the patient was permitted touse up to the remaining amount of Tizanidine, but not more than a totalof 8 mg for the night if she awoke during the night and found that shecould not fall back to sleep. This was not necessary, and once asleep,she was able to sleep through the night waking infrequently but rapidlyfalling back to sleep.

Safety monitoring included making certain there were no issues withliver function, low blood pressure or unusual dreams as this wasaccomplished. Tizanidine could, if needed, be dosed again during thenight without causing a morning “hangover” effect providing there was afour hour sleep window available.

HRT was not an option for controlling her hot flashes since this womanhad been diagnosed with hormone receptor positive breast cancer. She hadadditional challenges in the potential treatment of hot flashes becauseof the history of breast cancer. This was in part because she hadreceived chemotherapy which caused a peripheral neuropathy.Consequently, the hot flashes she experienced were perceived with evengreater intensity because the overwhelming sense of rising body heat wasin direct contrast to the constant freezing cold sensation of theneuropathy felt in both feet. In addition, she was receiving anaromatase inhibitor (anastrozole, 1 mg daily), a medication to block theproduction of estrogen and progesterone, in effect, anti-HRT. Thisfurther exacerbated the hot flashes into “super” hot flashes, a knownside effect of this type of medication. For her, the “super” hot flasheswere beyond the intensity of her previously experienced menopausal hotflashes. These hot flashes were crippling. They prevented her fromfunctioning normally, required that she bring changes of underwear andclothing to work, interrupted her sleep and interfered with her abilityto function in her normal activities of daily living. They impacted hersafety and the safety of others as well, regarding her ability toeffectively drive and accurately perform her job duties.

Other medication alternatives reported in the medical literature whichhad partial success in reducing hot flash frequency and severity by asmuch as 50% were evaluated by titrating to the doses reported, andmaintained at those doses for at least a two week trial. These includedclonidine at a dose up to 0.4 mg, gabapentin at a dose of up to 1800 mgand venflaxamine at a dose of up to 300 mg. However, these were notsatisfactory in reducing hot flashes by more than 25% in thisindividual. Therefore, following the unsuccessful trials with theseagents the focus was switched to a trial with a novel agent, Ropinirole,a dopamine agonist.

With Ropinirole, the goal has been directed at regulating GnRH, andcontrolling the unsuppressed LH pulses characteristic of menopause,through the action on D₂ and D₃ receptors within the hypothalamus. Priorineffective dopamine agonists that have been used for this purpose havehad opposite actions on these molecules because they worked on the D₁and D₅ receptors. The responses of the D₁ and D₅ receptors vs. the D₂,D₃ and D₄ receptors are diametrically opposed.

Ropinirole titration was initiated with 0.25 mg at bedtime, and iftolerated, by escalating the dose by 0.25 mg every fourth day to amaximum of 1 mg (i.e., 0.25 mg, 0.50 mg, 0.75 mg, 1 mg), until there wasreduction in both the frequency and severity of hot flashes. If higherdoses were needed, then both 1 mg, or later 2 mg and both 1 and 2 mgRopinirole tablets were used along with the continued titration by 0.25mg steps every fourth day until a maximum of 4 mg was reached. HigherRopinirole doses were not needed to accomplish clinical suppression ofthe hot flashes in this woman, but were not tested either due to agreater likelihood of side effects such as nausea, hallucinations orjitteriness.

With this protocol it was possible to provide aide to allow this patientto fall asleep within 15 to 20 minutes, rather than tossing and turningfor up to two hours before falling asleep. In addition, this patient wasable to sleep through the night for seven to eight hours on thistreatment, while without treatment she had been awakening anywhere fromtwo to three times per hour once she did fall asleep.

The combination of Ropinirole and Tizanidine represented a newcombination that provided aide in falling asleep, staying asleep andproviding significant additional relief by completely eliminating thefrequency and severity of hot flashes that this patient had experiencedprior to treatment. This was a highly significant and dramaticallynotable improvement compared to any prior option available. Ropinirolewas shown to reduce hot flashes as a dopamine agonist on the D₂, D₃ andD₄ receptors. The new combination of Ropinirole and Tizanidine wasadditionally effective in totally eliminating the most severe form ofhot flashes, with the most intense vasomotor symptoms. It completelystopped the frequency and intensity of these symptoms. When the dose ofRopinirole was removed, the symptoms returned. When the Ropinirole wasre-administered at 4 mg, the hot flashes once again disappeared.

Case #2

JM is a 52 year old woman with multiple sclerosis (MS) for 26 years. Shehad been experiencing difficulty with vision, inability to walk due tospinal symptoms, severe neurogenic bladder with incontinence, fatigueand multiple hot flashes throughout the day causing severe sweats and asensation of heat overcoming her body. Ironically, with the sensation ofheat there was an overwhelming sense of weakness and fatigue. Thispossibly reflected what is known as the “pseudoexacerbation” phenomenonin MS. Central nervous system (CNS) nerve fibers that already arephysically damaged, but somewhat physiologically compensated, can losetheir ability to compensate as body temperature rises. The function ofthese nerve fibers can improve once again as body temperature cools.

Patient JM is extremely temperature sensitive and wears a cooling vestto remain on the cool side for this very purpose. Prior to treatmentwith Ropinirole for the regulation of her hot flashes, IM had beenexperiencing anywhere from 15-20 hot flashes per day, with severeflushing of the face and chest and associated weakness. She attempted tocool herself with a hand held, battery operated fan and by drinking icecold liquids. While that effort provided some improvement of symptoms byshortening the duration of her hot flash associated weakness, it did notprevent the recurrent episodes. Hormone Replacement Therapy (HRT) wasnot an acceptable option for her due to her high risk profile for DeepVein Thrombosis (DVT) because of her immobility due to paralysis fromthe MS, and her smoking history.

She was using Tizanidine for treatment of spasticity and the dose wasadjusted to provide 8 mg at bedtime to facilitate sleep, which it did.In addition, she was titrated up to a Ropinirole dose of 4 mg daily atbedtime which totally eliminated the vasomotor symptoms (hot flashes)without side effects. In addition, there was also resolution of the MSpseudoexacerbation phenomenon. The combination of these two agentsprovided a new product that aided her falling asleep, staying asleep andcompletely eliminated her hot flashes of menopause, in a circumstancewhere HRT was contraindicated due to high risk of vascular complicationsfrom immobility and smoking (DVT).

Case #3

DH is a 53 year old woman with multiple peripheral nerve injuries anddiabetes. She entered menopause two years ago and developed themenopausal symptom of hot flashes with a frequency of 15-20 hot flashesper day, with each one lasting 15-30 seconds in duration. There wasflushing and reddening of the face and the chest, with associatedbeading of sweat, during these hot flashes and they interfered with herability to obtain a full night of normal sleep. She had been able tofall asleep with the use of sedative hypnotic medication, temazepam,even prior to the onset of the hot flashes.

After the onset of the hot flashes she noted difficulty sleepingthroughout the night because of drenching night sweats associated withthe hot flashes after which she would feel very cold. HRT was not anacceptable form of treatment due to metabolic issues with the control ofher diabetes. She then received the combination of both Tizanidine,titrated up to 8 mg at bedtime, and Ropinirole, which was also titratedas with the other patients. Her sleep improved and her hot flashescompletely resolved at a dose of 4 mg at bedtime with no untoward sideeffects.

Cessation of the hot flashes, combined with uninterrupted sleep not onlyleads to a more productive work day, but a safer day as well, regardingsuch activities as operating an automobile, where alertness isimperative. Her diabetes remained under excellent control.

Case #4

PW is a 48 year old woman with a chronic neuropathic pain disorder whoentered menopause at a younger age than most, but developed hot flasheswith drenching night sweats as significant symptoms like most. The hotflashes were associated with facial flushing and flushing of the chest.These episodes lasted 15-30 seconds each and would occur 10-15 times perday. She already was under treatment with clonidine, gabapentin andvenflaxamine for her neuropathic pain and associated depression, anddeveloped these hot flash symptoms despite those medications. HormoneReplacement Therapy (HRT) was contraindicated because of the potentialfor worsening her depression. Tizanidine 4 mg was titrated for sleep to8 mg at bedtime, and treatment with Ropinirole was initiated andtitrated to 4 mg at bedtime. She slept and on the Ropinirole 4 mg atbedtime she had complete resolution of the frequency and severity of thehot flashes without untoward side effects. She previously had manifestedirritability and difficult concentrating which seemed to improve as thehot flashes abated and sleep improved.

The combination of these two agents represents a new combination thatprovides aide in falling asleep, staying asleep and providingsignificant relief by completely eliminating the frequency and severityof hot flashes which were resistant to other medication described aspotentially useful in the medical literature. HRT would not have been anacceptable alternative for this patient because of the probability of ithaving a negative impact on her already altered mood state associatedwith her pain disorder. This new product was effective in totallyeliminating her intense vasomotor symptoms (hot flashes), and improvingher ability to sleep.

Two of the most incapacitating symptoms of menopause are hot flashes anddisruption of the normal sleep pattern. Although there have been manyattempts to address each of these symptoms individually, treatmentmethods thus far do not adequately resolved symptoms, and many have alsocreated additional health risks. Further, no singular product hasaddressed both of these symptoms.

The subject invention describes a novel and new use of Ropinirole toalleviate and control menopausal symptoms in women, and in particular,hot flashes. As a dopamine agonist, Ropinirole is believed to bind tothe D₂, D₃, or D₄ receptors, particularly at the D₃ site. This affinityinhibits production of GnRH which reduces production of LH and FSH inthe pituitary. LH and FSH are vasodilators, and lower levels of LH andFSH result in reduced incidence of hot flashes.

Clinical studies have shown that treatment with Ropinirole significantlyreduced hot flashes and menopausal symptoms. The use of Ropinirole as amenopausal symptom treatment overcomes the limitations of the prior artas it does not pose some of the significant health effects and sideeffects associated with other treatment methods. Further, clinicalstudies have shown the use of Ropinirole to have a much greater efficacythan traditional menopause treatments.

The combination of these two agents, Tizanidine and Ropinirole,represents a new product that provides aide in falling asleep andstaying asleep and provides complete elimination of hot flashes inexperimental studies.

The invention has been disclosed in terms of preferred embodiments whichfulfill all of the objects of the present invention and overcome thelimitations of the prior art. Various changes, modifications, andalterations from the teachings of the present invention may becontemplated by those skilled in the art without departing from theintended spirit and scope thereof. It is intended that the presentinvention only be limited by the terms of the appended claims.

What is claimed is:
 1. A composition for treatment of menopausalsymptoms, comprising: a substance that is a dopamine agonist capable ofbinding to D₂, D₃ or D₄ dopamine receptors, and a substance havingsedative effects, wherein the dopamine agonist is Ropinirole and thecompound having sedative effects is Tizanidine, and wherein thecomposition is provided as a unit dosage in an amount of Ropinirole in arange from 0.25 mg to 4 mg per day, and in an amount of Tizanidine in arange from 1 mg to 8 mg per day.
 2. A composition as set forth in claim1 wherein compound A and compound B comprise a pill form.
 3. Acomposition as set forth in claim 2 wherein compound A and compound Bare separately placed within the pill.
 4. A composition as set forth inclaim 2 wherein compound A and compound B are combined within the pill.5. A compound composition as set forth in claim 1 comprising a formwhich is capable of administration to an individual orally as a liquid.6. A composition as set forth in claim 1 comprising a form which iscapable of administration to an individual intravenously as a liquid. 7.A composition as set forth in claim 1 comprising a form which is capableof administration to an individual by inhalation.